Studies XIII.

Hemoglobin

on

Abnormal

Hemoglobins Disease
in

S-Thalassemia Thalassemia Disease

and Siblings
SINnER,

Hemoglobin

C-

By

I1tL

Sixuiit,t

AAuox

\I. ,JosEPmIsd)x, Liix Hytx J. ZmuuEutnN

STUDIES have the beeti double

PAUL

HmLLEIm

ANI)

S
cell
genes.

LilICIENT microdrepanocytic

FAMILY disease

reported

demomistrat.ing
state for

that
the

represetits

heterozygous

abiiormiial
patterti

sickle
is that

cell to the

hemoglobin satne

and
of the

the

thalassemia
genes

genes.4
for

The interaction
amid

inheritance
amid sickle

of tratismission seems case no and a.n(l analysis standard from elect rophoretic component by rophoresis demouistra.ting for means of

non-a.llelic

thalasseniia

henioglobin
The

pattern Recently, with present

itidlividual, to be the
have

mnost
samne

frequently
in C-thalassemnia

with rating latter

of these

E-thalassemia

diseases. thes.e genes try

reports

appeared
interaction.4

demotist
These

demotistrable of diagnosis discuss. in that the usual seeti pattermi

the inheritance of discoveries pose a which this disease which

is

problem
will means anemia. Hb be

of genetics
to

of the
case in

hemoglobinopathies of sickle
reveals with of F, a major Fib A, or

paper
by

Hemoglobin

cell-thalassensia a pattern
(homnozygous) comnponent Fib atid F alone.3 alkali

of the
The

electrophoretic

techmncs patietits is that A + alkali moving various is that sickle

often cell
by F may

indistinguishable
S, and demotistrated of elect a minor

sickle
furmiished lib

of lib the these disease A fraction iure (preferably

detiaturation
boimndary)

technic.

(omnbinitig
denaturation

t.he pattern Occa-

technics is necessary

seemi in microdrepanocytic sionally,

drepanocytic requiring features. A most intriguing aspect
genetic

patterns. of the S + and anemia4 the

Classically, the A + F grouping.3 differentiation

be quite hemat
91 mma

however, disease

the studies

HI) from

is lacking cell
evaluation

of microdifficult,

and

perhaps

of cert
disease of the

ai a ot her
frequent.

ologic
of

of Fib

S-thalassemnia hemolysate

is the affected

finding

high
This of Hb

percentages
phenomnenoti A forunation of the

of Hb
has by the gemie

S in the
beeui for the thalassemia

individual.3

interpreted getie, abnormal

to

represent
or enhancemetit3 by

either
the

suppression3
of production thalassemia or gene.

of

expressivity

hemoglobin

In semia

a preceding paper of this series,15 two disease were described. ilematologically,

Negro
they

patietits
showed

with

Fib

C-thalashypo-

a microcytic

From

the

1)epartment

of

Hematologic
merit of

Research,
Medicine,

Medical
West

Research
Side in aid by \.A. part. of

Instittmte,
hospital,

Michael
Chicago,

Reese Hospital and Illinois. The 1)epart mciii of Research Foundation. States Public Health L. Rot.hschi 1(1 Foundat Submuitted Oct. 24,

the

.1)epant

Hemsiatologic

Research

is supported

This work was carried otmt with the Service, and also supported in part. ion for Scient i he Research. 1956; accepted Feb. 17, 1957. 593

a grant

the

t lie Michael Reese from the United ilulda II. :113(1 Maurice

by

594 chromic erythrocytosis.

STUL)IES

OX

.o msxomtM.L

11E%IO(Ld)IIIXS

Hetnoglobin

analysis

revealed

the

jrcscnce

of

about

73

per cent of Hb C in association tively. Thus, a patterti for Hh S-thalassetuia

This with normal Hb paper

with Hb C-thalassemia
and with the by

A, or a mixture of lib A + F, respecdisease simnilar to that seeti itt Hb

genetic Hb father who features of afflicted two with siblings, one

disease
reports 5-thalassemia

was the were and

uncovered. hematologic the other supplied

C-thalassemnia
was

disease.
Hb

The C + although

abS

heinoglobins

disease, definite

and the thalassemia thalassemia.

gene

by the

mother

who

had

a ery

mild

\IET1IODS

Hemoglobin

ailalVses in

were

l)erformi3e(I at was

wit Ii I he pH that data (letermined 6.5,

of

technies and
Kimnkel

of paper
and

alkali
Wallenirus

(lenattmration,6 at as Hamilton pH

elec8.6.18

trophoresis The technic fled in this

ardized

the Tiselius apl)aratus of starch electrophoresis laboratory.9 20 Hernatohogic

Serum iron was by

electrophoresis with the of robe.23

ANALYsES

partially
et al.,22

modist.an(1:uid

were 1w wright
HEMOGLOBIN

obtained the and Wint

conventional

procedures.2

nwthod

iron

binding

globulin

as described
CASE
REPORTS

Cart
ANI)

\V., a 34 yr. old colored male, 11:1(1 been diagnosed as having sickle cell-Hb at another hospital. The nature of the henloglobinopathv was established by electrophoretic hemoglobin analysis (figs. 1:011(1 2).* He had been admitted to the hospital for a leg ulcer in 1948, and for a unilateral ophthalmic (vitreotms) hemorrhage in 1951. P.E. revealed heart and lungs normal; liver, spleeni, and kidneys not palpable. Radiographic bone survey was negative. Henatologically, the pat ient had a compensated hemolytic process (table 1) as evidenced by a retictmlocvte count of 3.6 to 7.4 per cent wills a red cell level of 4.6 mill. There was no evidence of bleeding. Numerorms target cells were seen in the film. 1 .-Retmben

C disease

Investigation

of

the

patients

family

was

prompted

by

the

statement.

that

his

wife

was

normal, however one of his children 11:0(1 died of sickle cell anemia. 2.-Bernice W., 27 yr. old Negress, wife of Heuiwn W., was an apparently healthy mdividual, except for a marked (hegree of deafness which developed after an episode of measles during her childhood. Her family history is non-contril)utory. No members of her immediate family were available for stimdy. P.E. was essentially normal except for tile deafness.
As test fetal
in

may was

be

seen target.

from The cells

was apparatus

table (26

1, the per
(fig.

reticulocyte blood filnl The

by the

level revealed osmotic method the of the of

is

within

nornlal

limits. the

The

sickling of

negative.

peripheral
demonstrable

sonw fragility alkali Rb total A. Jresenie

ovalocytosis

numerous the

cent).

was
of

and markedly

presence

decreased.
Electrophoresis

No
which desig-

hemoglobin Tiselius slightly here as A2,j

denatimration. a minor

1) demonstrated the to 10.2 main per component, cent.

component compomient., The Tiselius

migrated nated phoresis sis, as carried with

faster amounted

than

This

minor

hemolysate.

electro-

was performed compared with out thalassemic at pH 8.6.

at a pH the main Such 11 of this small It in

of 6.5, A7 was therefore faster with this component A, than in the starch elect component referred Recently, to had
as

type of elect rophorerophioresis which was observed component demonstrated means of starch in patients (tiC.) this elec-

a faster was series.3

Previously the unidentified

been

syndromes. component,

in communication hemoglobin

Kunkel

:111(1 \Vallenius hemolvsates by

amounts,

in normal

We

are

indebted

to Mr. 1)10(3(1

C.

Schlutz

at

the

Michael

Reese

Research

Foumidat

ion

for

the

determination
ics

of the

groimps.

f The classification of the subtypes of normal a(Itilt Rh was given at t lie Panic! on Genetof Hemoglobinopathies at the VIth International (onigress of Hematology, Boston 1956, as follows: symbol A, for main coml)onent , A2 for slow component, :uid A3 for fast

component.

sixi;iit

F;T

AL.

393

C63.7% 5:36.3% I

,.

________

(U.C.): 10.2% I

;w-1

5: )i.fl, A

L43,

Q/,

5:38.0%
to e dtntk*% udib

N
list COmpOn(nt

9.0%

NI0.9 A: 7.S%
(Uncfastst% (Iniponent)

5WIIS

U.C.
a
It ems

vouskj

tncountertd FIG.
1 .-

in some

tbcalasce.mIc. elect rol)horesis

sjndrome
on

(see
Vs.

tat)
fami

St auulam(l

lv

Pflerns Reuben

Pcit(snts ().(?otb.r

Eeelc4

Lu.

(11oth.r)

Pc1trki) 5#{231}s.

r4.eve,

JS4Ps.

Fm(;.

2.--Resi,lis

of

h)al)en

elect

rophioresis

studies

on

\V.

family

596

STII)IES
TABLE

OX

ABNORMAL
Data

HEMOGLOBIXS
on H. Fa?ni!!,

1.-Henialoloqir

:
,

-I
1: -. -

..

.ii ..s
. .

HH
1.

=
_

10

80

Patient

:
.

Diagnosis

=
.

E
. V

H
nR_p

, ., #{176} .-.

..

a
,

,IJ

a.
.

80 ,

_____
Reuben Berniee Patrice Sena Steve Gregory (father (mottier

80 l)

) E

C
O.44-O.2244.5

34
27 5 4

ni

HbC+Sdiseas Thalassemia
,

m4.4 4.6 44 95
titinini,

:3m.332.7
29231.0

35_741

m.3 63
0.9
Ci 0.6

m2.3
m3.0 u2.9

4.2
4.2 4.5

37
17

55
55

0.4-m.2
0.4

O.32-O.m626.O
0.4S0.32

180
73

420
420

,f
f ni
F

Sickleceiltrait Sicklecelitrait Fib 5-t1ia1asseriiii

30.935.m
27.33m.2 26.0 35.5,

to Sm 20033.0
25 29 71 72.5

1.0
4.2 1. m

0.40-0.32

m.4 0.8 118 468

.6 0.8 118 120 383 420

7.9

1.5 4.0

0.40-0.2231.4 0.22-0. m2 53.0

disease lib

11m
di8Fli..8e

C-tuiahtssemia

,mO.4

_____
our in own this

_____

All

l)atieflts

were

blood

type

eDe

MN.

trophoresis

arid

found
found of correlates A2

it to h)e increase(l
an as increase (letermnine(l very well with in

in

Ihialassenlimo all starch l)atients

nunor. itis

In

laboratory
50

have consistently ied. The amount per (cut.. This

iii A7 in

thalassemlia fast noving

niiilor patient

far was

stud-

electrophoresis

9.2

in the Tiselius electrophoresis. it seemed warranted to assulne

minima).

Because
t hat. Mrs.

the aniount of the of these hematohogic

\V. and child had a mild forns

conlj)onenit

note(l

and
of

ehectrophoretie
thahassensimi

findings
(I halassemia for having cell per revealed thse heart felt iron the below the trait cent.
ii

3.-Patrice sickle pat.termi 5.-Steven The grade lungs left blood However, uncovered 1 and per cent) 2). capacity film hemmitologic II systolic to costal cell trait W., (table 4.-Sena

\V., aged

5 yrs., 4, was

was also

climsically
I and 2). a healthy

hematologically
except for the

normal
demonstrah)le anemia. ins tah)le chest spleemi of the

except

(table 1; figs. W., aged indices murmur Liver

1; figs. 1 mind! 2). 3, showed and over was range

sickle 7.8 1. Gm.

a hypochromic other the base bone of

in

microcytic mire recorded heart; but. the x-ray tip of the

Hb

particulars of the survey the palpable, normal.

P.R. lie and oni

showed could irons seers paper cell nons-S major

amid

be normal. margin. were (fig. within 3).

not

A radiographic the Hematologically, analysis boundary by agreement of alkali Hb by S and alkali between resistant the indistinguishable

was normal. Serum A few sickled cells were

that found revealed by Hi) The anemic is normal. family, mind 53.0 microcytosis normal. the stat,e(l.* components ordinarily was large wit Is the amount This pattern a slower amounted fraction slower (Hb His per of Hb mis by the movinsg to
found

bin(hing

Peripheral
(hisease.

picture apparatus that

S-thmilmissemimi sickle ansemia component fraction. cent. Tisehius rsoted The film iron

hemoglobini a pattern The

was

Tisehius from

mis well ins classic that

electrophoresis (figs. (91 Fetal There apparain the is,

moving
provided

electrophoresis the remainder denaturation, t.he non-S hemoglobin.

hemoglobin, therefore, tus and the was MCH greatest was means to the from amormrits, At the are Tiselius and the test binding by due tiated equal cedtmre

as excellent amount

determined

10.0

per fraction per

in the

moviusg 10.4 Cm.

thus
W., number

composed
age

of Hi)
although

F only.
was the seen was technic slightly MCHC in t.his cent). blood (fig. the Hemoglobin alkali of Hb is Rb old 4). The serum

6.-Gregory

18 months, cells the boundary F + patient. cannot, Hb P.R.

MCV
reveals cell iron pro-

decreased I)espite were moving a C + of the Hb and of

peripheral cent.

of target normal.

sickle and

negative. globulin of the uncovered age the

hypochromia

essentially irs conijimnctioti Whether

electrophoresis denmituration F found readily present C is is pmortly diflerersin

A pattern.

A -1- C trmut from writinsg imrschanged pure this

as yet lie ins which 1)0th

C disemise this wisere patient

mire usually only

about
11-14. 24

found.4

time remained

pmtper,

24 months

ams(l the

amoumnst.

of

Hb

F had

SINGEII

ET

AL.

597

.4

$p
#{182}
,

-...

11

3.-

Peniplseral

1)1(10(1

srssean

iii Rh

S-I

halasseisiia

disease

( pot

ieni I St eve

\V.)

9
9

I
4,

IIG.

4 -Peripheral

1)100(1

smear

iii

Rh
pen

(-I

hialasscmnia

disease

(pat

iemit

( negorv

Vs.

Microspherocvt

osis

was

miot

ed omi the
to ailed I mesenice

Phiemal
sali use

1)100(1 smisear.8 fuagili sphelocvt

tv

The A 24

riiimsil hour
i

er nerd

of t hiese )ate(1

cells
saliuse

was
fragili

appa
tv

uemit lv insufficient

the of

st rmdy.
(5

di (I nsot

reveal

I lie

t hiese

l)iscussiox

The It

diagnosis confused depends

21. 26

oh

thalassemnia with on tlsat serum gemietic to and iron

of

minor

is

occasionally anemma, measurement. Most The

Isas

rat her and of the of the

difficult. different ervthrocvt.e elect differential starch Isematologist

to establish. its1 diagnosis protodiagnosis rophoresis

is often

iron inns

deficiency studies,

frequently porphyrin,1 is based as described on

an(l
response

evaluatioti. therapy. \Valleniusu

often techtiic provided

the by

Kunkel

with

598

5Tti)1E5

(IN

.1iNo1tM.tL

I1EsIoGLOIitN5

1.ibC.S

dstase

lhalassuuio

mnmo

(Th
died rrom
ciemcs

(Th
c.tIl sc.kk trat cdl lSihaiossemnks

_
ClhoIassdaa

sckk

sk%th, ctU

trcst

,eQk

Thatcs;siic
.: i-lb

9(1St

fcd.
d.Qd
FIG.
).

C QcnC

eniei

ic (1:11 a

(01

\\

ansi

lv

relat
rf}5(5(,

i velv
workers

inlpl( found

nset hod
that
,

t( r slet ermsnr sat i( us of hensolvsat es d)f iiormisal

component
,

t lie blood a fast results

acccssomy split. iiito component arc

,

hcmuogl( )I )i mis. three fractiomss,

,

usairs

conspousent

A1; a slow
in our

A2; ari(l our

A.

\Vc have the

same

confirmed as those
of

this Kurikel
ito

work

laboratory2 The

aiid
slow less

essentially

amid and In

\Vallemsius. it is between the few no were

mogain

corsipomierit

A7, amounts

to less

thais

3 Per
mitior

(emit

dcl icierscv tory patient,

sennia

iiorrnal anemsira, st tidied. by

Isemuolysates.

It is
cases clevat of great
have disease.

tliami

..

3 arid ions aid art

10 per
of iii

P(r cent ((mit in all major found.

in most cases of iron cases of thalasscmuia sttmdicd These in our fimsdings labora-

so far atid
_\

of tlsalassensiia A2 was
est iI

also irs. family to

I )r.

Kunikel, \V.,
ive

irs our

Bern ice stu(.ly

1i shi rig t Ise presence

of ant

of t halaswlsich is

minor.

In not

this due

instance

+
lie safely and
cmiusc

F pattern stated studies of this family

horsiozygous S +
to

sickle diagnostic lIb out

cell

It rutty
ariensia, as t lie til
.,

that
hemsioglobin

the
tsiay

phenotype be msecessarv

I is riot rule Smuith

li)r sickle

cell

5-tlsalassemia

disease

analysis reported
lhe with each abnormal lib is marrifest interaction

patterns. this
dottble type in this (-thalasscmia of the The

amid (onley,9
in

It aniii

ct

ams(l Zuelzer
disease.

hav(
arid

Pm(\D)tt5lY

of pattern
state

Fib S-thalassenuia for pat (fig. t.lsc abmiormual

ierst with

hctcrozygous family mobriornsal child as

lscrisoglol S family there the disease child

iii)

t he thalassemia disease amid of ma;ked thalassensia per cent.

of

one

lib with 1). The

thalassemia gcrsc(s) has with for

91

one ins the

disease with

5).

Irs this gene

is evidence

hemoglobin Fib hcmolysatc

iristamicc.

S-thalasscnuia (fig.

hemoglobin

in his

Fib

(-thalasscmia

SINGEII

ET

AL.

599

5.n.W.

Cog; fl, suenc

1hsePc.

of of
s

ik#{248}Iose,snsa thcnslassem(cs That wbc.I) iuos csccepttd (ln2rtis.

of

The above termnologs

at The

bj The Ponsi on Genet(cs

of 14emo 9S6.

6Th IntQrnatont
Fio.
6.-Gemiotvpes

o
fanisi!y

I-kmotoloij,

Boston

\V.

Tb

hoIo

9!!..

AA

2SOanc4lnsnt

of c.bnormol .!i!!!.Io$s#Mc.

hc.noglobfn 9t

ffL,_IffiP!.

9!!!.

fbotasu.fa

9.

5.Thalosst.sia

and/or

*.ckI. M of mu(t.pk

dsscast 5.ktd QMS

Thastemca

S
),,

qo.o
I mince of :11 )!i( nmssa

Fmo enice
of

7.

-Possi

hie genet

ic I iieori

es

for

i niheri

henssog!ol.d

us

in

t he

I )nes

I hialasseisia.

disease

has abnormal

81 .3 per

(emit

lib

C (fig. (fig. (i).

).

These

pat iemit s received the muarufcstat

omily

omic genie

for

the

hemoglobin

Iheoret-ically,

ions of this

genie
of the

in the individuals receiving just one getic should be either equal amounts abmiormal hemisoglobin and HI) A, or less than 50 per (emit of the abnormal globini, as iway I)e seems iti all cases of the sickle cell trait ii. 2-i (.)I.)viously
.

hcmsiosonicin the

thing

has

affected

the

expressivity

of the

gene

for

the

abnormal

hemoglobin

600 cases under consideration. inhibits

STUDIES

ON

ABNORMAL

HEMOGLOBINS

Previous or suppresses the

workers production

have

postulated of Hb A.3
. .

that

the

gene

for

t.halassernia

Considering

that

the

thalassemia gene is a single gene, one must. attempt to explain the phenomeof no suppression in the mother of this family, with almost. complete supptession of the production of Hb A in the children manifesting the double heterozygous state. An explanation for this phenomenon may be the effect of modifying
non

genes.
which

Another
have

way
multiple

of stating
genetic

the

problem the

is that
(fig.

we 7).

may A

be dealing
number of

with
reports

diseases
have

causations

appeared

which

have

demonstrated same the Humble

had

inheritance

of an

al)normal

hemoglobin of the a thalasand 22.3 a family minor, yet et al.7 of with

and thalassemia in the genes. Neel et al.4 report semia per

in which

individual occurrence of Hh

with no evidence of interaction of Hb S trait accompanied by patients were 36.2, 27.7, have also reported and a t.halassemia of t.he genes. child showed a simple sickle

minor. cent, one

Hb three

The

amounts

S in 3 such

respectively.
children

et al.6 from England inherited a Fib S gene evidence muselman

gene and

only report
the

of the
S with

three
the

had

any

of interaction in which
another

Roche interaction cell trait

a family

of Tunisian
thalassemia

one
had

thalassemia the patient would seem The has

minor. Zuelzer8 reports a ease of Hb C-thalassemia had only 29.0 per cent Hb C. One of two prime to be manifest in the inheritance of the double gene may be present in two different ability to interact with the gene for have this ability. geties. No definite prefer seen

disease inheritance heterozygous

in which patterns states.

thalassemia the intrinsic

forms, i.e., the abnormal

a gene which hemoglobin of the

or one multiple available. marked

which does not or modifying The clinical authors variations

The other possibilit.y is the presence answer to these problems is presently as this form would help of t.halassemia. explain

the latter theory in the heterozygous

In sickle cell anemia there is also some evidence one gene involved. Zarafonetis et al? have recently found in patients with homozygous sickle cell degree, than in patients to the pleiotropic t.heory
have Whereas

that there may be more than shown that the hyposthenuria disease is present, to a larger There seems to be no relation of It is also quite possible the renal concentration the fact
from compensate

with

the

sickle of Hb
might

cell trait. S present.

produce

the hyposthenuria single gene with A multiple

sickle cell dividuals.24

amount effect would

a marrow the normal

that a defect. with

inits

gene
anemia
28

possibly

also
marrow

explain
different can

that
that or

patients
of normal increase

regulation

erythropoiesis with sickle

patient and tion, curve and

some six to eight times its normal level,29 the marrow of a patient cell anemia has only a fourfold increase of red cell production.3#{176} A with sickle cell anemia who receives transfusions to a normal red cell
level will have a marrow of radioactive showing iron very from little the or no plasma red cell will populashow a the disappearance

hemoglobin similar

to be

that

seen

in

aplastic

anemias.
on

The presence

causation of Hb

of these S alone.

various we

defects

cannot

logically

explained

the

If then

are dealing with diseases possible to explain the states

the

which various
or

are controlled inheritance of genes

on t.he

by more than patterns of the which are

of

one gene it becomes double heterozygous for interaction

of such

on the
abnormal

basis

of transmission

specific
transmission

with
genes.

henioglohins,

absence

SIXGE1I

ET

AL.

601 disease
hemoglobin

The
been

majority
nianifest.

of cases
by
24

of Fib index
of

Sof those

on Hb
the

C-thalassemia for
having

so far
greater

st.tndied
than 60

have
per

ansoumits determine use those

abtsormal

cent..4
l)e

In-n4

A high
to The with

of suspicion
cases starch

the

double
small should

het.erozygous
amounts prove or patients of the

states
abnormal extremely having

may
helpthalas-

niecessary

hemoglobin. ful sensia in uncovering together

electrophoresis of very mild thalassemia,

cases

abnormal

hemnoglobins.
SUMMARY

A family
and

study

is reported
disease is

in which
noted.

the

simultaneous
interaction

presence
of the

of C-thalassemia
genes for the

5-thalassemia

Marked

abnormal The
The anemia. patient and an

hemoglobins value
Hb may abnormal

and accessory
can all genetics to

for

t.halassemia

is evident. for the diagnosis

t.o be the of the

of the
S +

hemoglobinis
no rule longer out.

of t.halassensia
diagnostic background thalassemia states for gene. of sickle

minor
cell of the

is discussed. F pattern of necessary of the hemoglobin be assumed data the double and presence Evaluatiots be hematologic of the family

A discussion

heterozygous

thalassemia

is presented.
SUMMARIO

ix
ins que
e de

INTERLINGUA

Es
es

reportat.e
Marcate pro

un
C plus

studio
grados

fansilial
de

le presentia
de del hensoglobina pro pro genies

simultatiee
S plus le hemnoglobinsas le diagnose de esser ciue de

de

morbo
t.halassemia anormal thalassemia

de

henioglobina
notate.

thalassemia

morbo

interactions es evidenst.e.

con Es

le genies diseutite ha devenite

thalassemia le valor de

hemoglobinas comisiderar a cellulas e he historia

accessori le

mimsor. Il comiso omne Es impossibile de pote e un anemia tsegate. discussions dcl gensetica de duple st.atos heterozygotic pro ansormal.
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